WO2000066614A1 - Steroides substitues par heterocycle 3alpha-hydroxy-3beta-methoxymethyl-21- ayant un pouvoir anesthesique - Google Patents
Steroides substitues par heterocycle 3alpha-hydroxy-3beta-methoxymethyl-21- ayant un pouvoir anesthesique Download PDFInfo
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- WO2000066614A1 WO2000066614A1 PCT/US2000/011680 US0011680W WO0066614A1 WO 2000066614 A1 WO2000066614 A1 WO 2000066614A1 US 0011680 W US0011680 W US 0011680W WO 0066614 A1 WO0066614 A1 WO 0066614A1
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- Prior art keywords
- compound
- methoxymethyl
- hydroxy
- pregnan
- optionally substituted
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- 0 C[C@](CC1)(C(CC2)C(CC3)C1[C@@](*)(CC1)C3(*)C[C@]1(CO)OC)[C@]2C(C*)=O Chemical compound C[C@](CC1)(C(CC2)C(CC3)C1[C@@](*)(CC1)C3(*)C[C@]1(CO)OC)[C@]2C(C*)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Definitions
- the present invention relates to the field of medicinal chemistry and to novel steroid derivatives and methods for modulating brain excitability. More
- the invention relates to 3 ⁇ -hydroxy-3 ⁇ -methoxymethyl-21- substituted-5 ⁇ - (and 5 ⁇ -)pregnan-20-ones with properties desirable for use as sedative/hypnotics and anesthetics.
- neuroactive steroids are unsuitable as sedative/hypnotics because they have poor oral bioavailability presumably due to rapid first-pass metabolism (Hogenkamp. D. J. et al. J. Med. Chem. 40:61 - 72 ( 1997)).
- the addition of 3 ⁇ -substitution results in neuroactive steroids that
- RrR 13 are individually selected from a large number of groups.
- the compounds are described as useful as anticonvulsants, sedative/hypnotics and anesthetics.
- R. R]-R ]0 are individually selected from a large number of groups.
- the compounds are described as useful as anticonvulsants. sedative/hypnotics and anesthetics.
- the present invention is related to 3 ⁇ -hydroxy-3 ⁇ -methoxymethyl-21- substituted-5 ⁇ - (and 5 ⁇ -)pregnan-20-ones with properties especially desirable for use as sedative/hypnotics and anesthetics.
- the present invention is also directed to the use of a compound of Formula I as an anesthetic.
- a first aspect of the present invention is directed to the novel methoxymethyl-substituted steroids of Formula I.
- a second aspect of the present invention is directed to the novel compounds of Formula I as sedative-hypnotics.
- a third aspect of the present invention is to provide a method of inducing anesthesia by administering a compound of Formula I to a mammal in need of such treatment.
- a fourth aspect of the present invention is to provide a pharmaceutical composition containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
- the present invention arises out of the discovery that novel 3 ⁇ - methoxymethyl-3 ⁇ -hydroxy-substituted steroids of Formula I have duration of action that makes them especially useful as sedative/hypnotics and anesthetics.
- the compounds useful in this aspect of the present invention are 3 ⁇ - methoxymethyl-3 ⁇ -hydroxy-substituted steroids represented by Formula I:
- R is H or methyl
- R 2 is 5 ⁇ - or 5 ⁇ -H
- R 3 is an optionally substituted N-attached heteroaryl group or a group -X-R 4 ;
- R 4 is an optionally substituted-carbon attached heteroaryl group;
- X is O, S or ⁇ .
- An additional group of preferred compounds of Formula I are wherein:
- Another preferred group includes compounds of Formula I where R 3 is an optionally substituted N-attached monocyclic heteroaryl group.
- Preferred neuroactive steroids include 3 ⁇ -hydroxy-3 ⁇ -methoxymethyl-21-(quinolin-6- yloxy)-5 ⁇ -pregnan-20-one and 21-(5'-amino-[l,3,4]-thiadiazol-2-ylthio)-3 ⁇ - hydroxy-3 ⁇ -methoxymethyl-5 ⁇ -pregnan-20-one.
- a more preferred group of compounds of Formula I are compounds where R 4 is the N-oxide of an optionally substituted carbon attached bicyclic heteroaryl group; and
- R is an N-attached imidazole or tetrazole that may be optionally substituted.
- 3 ⁇ -hydroxy-21-(l '- imidazolyl)-3 ⁇ -methoxymethyl-5 ⁇ -pregnan-20-one and its hydrochloride salt 3 ⁇ -hydroxy-21-(l '-imidazolyl)-3 ⁇ -methoxymethyl-5 ⁇ -pregnan-20-one and its hydrochloride salt, 3 ⁇ -hydroxy-3 ⁇ -methoxymethyl-21 -(2'-tetrazolyl)-5 ⁇ - pregnan-20-one and 3 ⁇ -hydroxy-3 ⁇ -methoxymethyl-21 -(quinolin-6-yloxy)- N-oxide.
- Useful compounds in this aspect of the present invention include without limitation: 3 ⁇ -hydroxy-21-(l '-imidazolyl)-3 ⁇ -methoxymethyl-5 ⁇ -pregnan-20- one;
- Useful aryl groups are C 6 _ ⁇ 4 aryl, especially C 6 ., 0 aryl.
- Typical C 6 ., 4 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl. biphenyl, biphenylenyl and fluorenyl groups.
- Useful cycloalkyl groups are C 3 . 8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl. cyclopentyl and cvclohexyl and cycloheptyl. Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as defined above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
- Useful heteroaryl groups include any one of the following: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl.
- tetrazolyl pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
- 4H-quinolizinyl isoquinolyl. quinolyl, phthalzinyl. naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, ⁇ -carbolinyl. phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl. isothiazolyl. phenothiazinyl, isoxazolyl, furazanyl. phenoxazinyl.
- Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
- Useful alkyl groups include straight-chained and branched C,., 0 alkyl groups, more preferably C,_ 6 alkyl groups.
- Typical C M0 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups.
- a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
- Useful alkenyl groups are C 2 . 6 alkenyl groups, preferably C 2 disturb 4 alkenyl.
- Typical C 2 . 4 alkenyl groups include ethenyl, propenyl. isopropenyl, butenyl, and sec.-butenyl.
- Useful alkynyl groups are C 2 _ 6 alkynyl groups, preferably C 2 . 4 alkynyl.
- Typical C2-4 alkynyl groups include ethynyl, propynyl. butynyl, and 2- butynyl groups.
- Useful arylalkyl groups include any of the above-mentioned C,., 0 alkyl groups substituted by any of the above-mentioned C 6 . 14 aryl groups. Useful values include benzyl, phenethyl and naphthylmethyl.
- Useful arylalkenyl groups include any of the above-mentioned C 2 . 4 alkenyl groups substituted by any of the above-mentioned C 6 . 14 aryl groups.
- Useful arylalkynyl groups include any of the above-mentioned C 2 . 4 alkynyl groups substituted by any of the above-mentioned C 6 . 14 aryl groups. Useful values include phenylethynyl and phenylpropynyl.
- Useful cycloalkylalkyl groups include any of the above-mentioned C,_
- Useful haloalkyl groups include C 0 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 J -difluoroethyl and trichloromethyl groups.
- Useful hydroxyalkyl groups include C,. 10 alkyl groups substituted by hydroxy. e.g. hydroxymethyl. hydroxyethyl. hydroxypropyl and hydroxybutyl groups.
- Useful alkoxy groups include oxygen substituted by one of the C 0 alkyl groups mentioned above.
- Useful alkylthio groups include sulfur substituted by one of the C M0 alkyl groups mentioned above.
- Useful acylamino groups are any C,. 6 acyl (alkanoyl) attached to an amino nitrogen. e.g. acetamido, propionamido, butanoylamido. pentanoylamido, hexanoylamido as well as aryl-substituted C _ (: substituted acyl groups.
- Useful acyloxy groups are any C,_ 6 acyl (alkanoyl) attached to an oxy (-0-) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
- Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl. piperizinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinvl pyrazolinyl, tetronoyl and tetramoyl groups.
- Useful heterocycloalkyl groups include any of the above-mentioned C,. 10 alkyl groups substituted by any of the above-mentioned heterocyclic groups.
- Useful amino groups include -NH 2 , -NHR 5 , and -NR j R ⁇ , wherein R 5 and Rj, are C 0 alkyl or cycloalkyl groups as defined above.
- Useful aminocarbonyl groups are carbonyl groups substituted by — NH 2 , — NHR honor and — NR 5 R 6 , wherein R 5 and R 6 are C,., 0 alkyl groups.
- Optional substituents on any of the heteroaryl rings in Formula I include any one of halo, haloalkyl, aryl. heterocyclo, cycloalkyl. heteroaryl, alkyl, alkenyl, alkynyl. arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl. heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl. hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido. cyano, acylamino, hydroxy, thiol, acyloxy.
- Preferred optional substituents include: halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro, alkyl. alkoxy and amino.
- Certain of the compounds of Formula I may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual entantiomers that may be separated according to methods that are well know to those of ordinary skill in the art.
- Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide. phosphate, sulphate, citrate, lactate, tartrate, maleate. fumarate. mandelate. acetic acid, dichloroacetic acid and oxalate.
- Examples of prodrugs include esters or amides of the compounds
- Formula I with optional substitution including hydroxyalkyl or aminoalkyl may be prepared by reacting such compounds with anhydrides such as succinic anhydride.
- the compounds of this invention may be prepared using methods known to those skilled in the art.
- compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
- the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg. or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for insomnia.
- the dose is generally about one-half of the oral dose.
- the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0J to about 10 mg of the compound.
- the unit dose may be administered one or more times daily as one or more tablets each containing from about 0J to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
- the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into reparations which can be used pharmaceutically.
- suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into reparations which can be used pharmaceutically.
- the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s). together with the excipient.
- non- toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope of the present invention.
- Acid addition salts are formed by mixing a solution of the particular heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like.
- Basic salts are formed by mixing a solution of the heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
- compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
- the pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral. subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route.
- the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any. frequency of treatment, and the nature of the effect desired.
- compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
- pharmaceutical preparations for oral use can be obtained by combining the active compounds, which may advantageously be micronized, with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch.
- flow-regulating agents and lubricants for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
- concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- cellulose preparations such as acetyl- cellulose phthalate or hydroxypropymethyl-cellulose phthalate.
- Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
- the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
- stabilizers may be added.
- Possible pharmaceutical preparations which can be used rectally, include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
- Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
- gelatin rectal capsules which consist of a combination of the active compounds with a base.
- Possible base materials include, for example, liquid triglycerides, polyethylene glycols. or paraffin hydrocarbons.
- Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
- suspensions of the active compounds as appropriate oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- the following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.
- 3 ⁇ -Hydroxy-3 ⁇ -methoxymethyl-5 ⁇ - and 5 ⁇ -pregnan-20-ones were prepared from (3/?)-spiro[oxirane-2 r , 5 ⁇ - or 5 ⁇ -pregnan]-20-one and sodium methoxide as described by Hogenkamp, et al., "Synthesis and in Vitro Activity of 3 ⁇ -Substituted-3 ⁇ -hydroxypregnan-20-ones: Allosteric Modulators of the GABA A Receptor.” J. Med. Chem. 40:61 -72 (1997).
- 21 -Substituted steroids were prepared from the corresponding 21-bromo steroids which were synthesized from the 20-ketosteroids using Br 2 in MeOH with catalytic HBr.
- the aqueous layer was separated and washed with CH 2 C1 2 (3 x 25 mL).
- the pooled organic layers were dried (Na 2 SO 4 ) and cone, in vacuo.
- the resulting residue was dissolved in CH 3 CN (100 mL) and treated with solid imidazole (5 eq.; 1.88 g, 27.6 mmol). After 1 h at reflux, the reaction was allowed to cool and concentrated to dryness.
- the residue was partitioned between CH 2 C1 2 and a sat. aq. NaHCO, solution.
- the aqueous layer was separated and washed with CH 2 C1 2 (3 x 25 mL).
- the pooled organic layers were dried (Na 2 SO 4 ) and cone, in vacuo.
- Table I below compares the in vitro potencies [ability to inhibit the binding of [ 35 S]-tert-butylbicyclophosphorothionate (TBPS)], rotorod TD 50 's (dose at which half of animals tested fail to stay on a rotating rod for 1 minute) and the length of time before all animals tested are able to pass rotorod test (duration of action) of closely structurally related pairs of 3 ⁇ -methyl and 3 ⁇ - methoxymethyl steroids.
- T3PS assay gives the in vitro potency of compounds whereas the rotorod assay estimates the sedative/hypnotic activity of compounds.
- the duration of action of a compound is dependent on the dose and will be prolonged at higher doses, the duration of action was measured at the lowest dose where all of the animals failed the rotorod test.
- duration of action > 240 minutes the number of animals passing the rotorod test at 240 minutes is given in parentheses.
- the 3 ⁇ -methyl steroid has a biological duration action of greater than 240 minutes, while in each of the corresponding 3 ⁇ -methoxymethyl steroids the duration of action is reduced to 180 minutes or less.
- the 3 ⁇ -methyl steroids show less than half of the animals passing the rotorod at 240 minutes, suggesting a duration of action significantly longer.
- IC 0 is the dose of steroid inhibiting 50% of specific binding of ["S]-.- ⁇ /- butylbicyclophosphorothionate (TBPS) RR TD, 0 is the dose at which half of animals fail the rotorod test in rat Duration of action, measured at the lowest dose where all animals failed the rotorod test, is the time required for all animals tested to once again pass the rotorod test . All patents and publications cited herein are fully incorporated by reference herein in their entirety.
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Abstract
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00930250A EP1177206A1 (fr) | 1999-04-29 | 2000-04-28 | Steroides substitues par heterocycle 3alpha-hydroxy-3beta-methoxymethyl-21- ayant un pouvoir anesthesique |
CA002372342A CA2372342A1 (fr) | 1999-04-29 | 2000-04-28 | Steroides substitues par heterocycle 3alpha-hydroxy-3beta-methoxymethyl-21- ayant un pouvoir anesthesique |
BR0010060-9A BR0010060A (pt) | 1999-04-29 | 2000-04-28 | Esteróides 3<244>-hidroxi-3<225>-metoximetil-21-heterocìclo substituìdos com atividade anestésica |
KR1020017013819A KR20020013530A (ko) | 1999-04-29 | 2000-04-28 | 마취 활성을 갖는 3α-히드록시-3β메톡시메틸-21-헤테로사이클 치환 스테로이드 |
MXPA01010915A MXPA01010915A (es) | 1999-04-29 | 2000-04-28 | Esteroides sustituidos con 3alfa-hidroxi-3beta mexoximetil- 21 -heterociclo, con actividad anestesica. |
AU48104/00A AU780989B2 (en) | 1999-04-29 | 2000-04-28 | 3alpha-hydroxy-3beta methoxymethyl-21-heterocycle substituted steroids with anesthetic activity |
JP2000615643A JP2002543218A (ja) | 1999-04-29 | 2000-04-28 | 麻酔活性を有する、3α−ヒドロキシ−3βメトキシメチル−21−複素環式置換ステロイド |
IL14623000A IL146230A0 (en) | 1999-04-29 | 2000-04-28 | 3α-HYDROXY-3β-METHOXYMETHYL-SUBSTITUTED STEROIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
NZ515779A NZ515779A (en) | 1999-04-29 | 2000-04-28 | 3alpha-hydroxy-3beta methoxymethyl-21-heterocycle substituted steroids with anesthetic activity |
UA2001118125A UA73736C2 (en) | 1999-04-29 | 2000-04-28 | Method for alleviating or preventing insomnia and inducing anesthesia |
PL00351438A PL351438A1 (en) | 1999-04-29 | 2000-04-28 | 3α−hydroxy−3β methoxymethyl−21−heterocycle substituted steroids with anesthetic activity |
NO20015262A NO321536B1 (no) | 1999-04-29 | 2001-10-26 | 3<alfa>-Hydroksy-3<beta>-metoksymetyl-21-heterocyklisk substituerte steroider med bedovende aktivitet |
HK02108656A HK1047594A1 (en) | 1999-04-29 | 2002-11-29 | 3A-hydroxy-3B methoxymethyl-21-heterocycle substi tuted steroids with anesthetic activity steroids with anesthetic activity. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13157899P | 1999-04-29 | 1999-04-29 | |
US60/131,578 | 1999-04-29 |
Publications (2)
Publication Number | Publication Date |
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WO2000066614A1 true WO2000066614A1 (fr) | 2000-11-09 |
WO2000066614A8 WO2000066614A8 (fr) | 2001-03-15 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/011680 WO2000066614A1 (fr) | 1999-04-29 | 2000-04-28 | Steroides substitues par heterocycle 3alpha-hydroxy-3beta-methoxymethyl-21- ayant un pouvoir anesthesique |
Country Status (21)
Country | Link |
---|---|
US (2) | US20040034002A1 (fr) |
EP (1) | EP1177206A1 (fr) |
JP (1) | JP2002543218A (fr) |
KR (1) | KR20020013530A (fr) |
CN (1) | CN1187367C (fr) |
AU (1) | AU780989B2 (fr) |
BR (1) | BR0010060A (fr) |
CA (1) | CA2372342A1 (fr) |
CZ (1) | CZ20013867A3 (fr) |
HK (1) | HK1047594A1 (fr) |
HU (1) | HUP0201818A3 (fr) |
IL (1) | IL146230A0 (fr) |
MX (1) | MXPA01010915A (fr) |
NO (1) | NO321536B1 (fr) |
NZ (1) | NZ515779A (fr) |
PL (1) | PL351438A1 (fr) |
RU (1) | RU2243232C2 (fr) |
UA (1) | UA73736C2 (fr) |
WO (1) | WO2000066614A1 (fr) |
YU (1) | YU77701A (fr) |
ZA (1) | ZA200109847B (fr) |
Cited By (24)
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WO2005105822A2 (fr) * | 2004-04-23 | 2005-11-10 | Euro-Celtique S.A. | Procede de fabrication de steroides 3-alpha-hydroxy sustitues, nouveaux derives de steroides et leurs applications |
US20060074059A1 (en) * | 2004-08-26 | 2006-04-06 | Goliber Philip A | Isomorphic crystalline habits of 3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha-pregnane-20-one |
WO2006131392A1 (fr) * | 2005-06-09 | 2006-12-14 | Euro-Celtique S.A. | Compositions pharmaceutiques a base d'un steroide neuroactif et leurs utilisations |
WO2010057455A3 (fr) * | 2008-11-21 | 2010-12-23 | Osram Opto Semiconductors Gmbh | Puce à semi-conducteurs à émission par la tranche |
EP3206494A4 (fr) * | 2014-10-16 | 2018-07-04 | Sage Therapeutics, Inc. | Compositions et méthodes pour traiter des troubles du snc |
US10172871B2 (en) | 2013-04-17 | 2019-01-08 | Sage Therapeutics, Inc. | 19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof |
US10246482B2 (en) | 2014-06-18 | 2019-04-02 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
US10323059B2 (en) | 2013-07-19 | 2019-06-18 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
US10329320B2 (en) | 2015-02-20 | 2019-06-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
US10377790B2 (en) | 2013-04-17 | 2019-08-13 | Sage Therapeutics, Inc. | 19-nor neuroactive steroids and methods of use thereof |
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US10426837B2 (en) | 2015-01-26 | 2019-10-01 | Sage Therapeutics, Inc. | Compositions and methods for treating CNS disorders |
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US11643434B2 (en) | 2019-05-31 | 2023-05-09 | Sage Therapeutics, Inc. | Neuroactive steroids and compositions thereof |
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ES2927007T3 (es) * | 2014-05-29 | 2022-10-31 | Sage Therapeutics Inc | Esteroides neuroactivos, composiciones y usos de los mismos |
EP3897656A4 (fr) * | 2018-12-17 | 2022-09-21 | Intra-Cellular Therapies, Inc. | Composés organiques |
US20240148756A1 (en) | 2021-02-18 | 2024-05-09 | Sage Therapeutics, Inc. | Use of neuroactive steroid for treatment of sexual dysfunction |
WO2023159035A1 (fr) | 2022-02-16 | 2023-08-24 | Sage Therapeutics, Inc. | Stéroïdes neuroactifs pour le traitement de troubles liés au snc |
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- 2000-04-28 NZ NZ515779A patent/NZ515779A/en unknown
- 2000-04-28 HU HU0201818A patent/HUP0201818A3/hu unknown
- 2000-04-28 CA CA002372342A patent/CA2372342A1/fr not_active Abandoned
- 2000-04-28 PL PL00351438A patent/PL351438A1/xx not_active Application Discontinuation
- 2000-04-28 WO PCT/US2000/011680 patent/WO2000066614A1/fr not_active Application Discontinuation
- 2000-04-28 JP JP2000615643A patent/JP2002543218A/ja not_active Withdrawn
- 2000-04-28 RU RU2001132583/04A patent/RU2243232C2/ru not_active IP Right Cessation
- 2000-04-28 CZ CZ20013867A patent/CZ20013867A3/cs unknown
- 2000-04-28 KR KR1020017013819A patent/KR20020013530A/ko not_active Application Discontinuation
- 2000-04-28 BR BR0010060-9A patent/BR0010060A/pt not_active IP Right Cessation
- 2000-04-28 CN CNB008083606A patent/CN1187367C/zh not_active Expired - Fee Related
- 2000-04-28 YU YU77701A patent/YU77701A/sh unknown
- 2000-04-28 IL IL14623000A patent/IL146230A0/xx unknown
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Also Published As
Publication number | Publication date |
---|---|
RU2243232C2 (ru) | 2004-12-27 |
JP2002543218A (ja) | 2002-12-17 |
NZ515779A (en) | 2003-11-28 |
HUP0201818A3 (en) | 2004-04-28 |
IL146230A0 (en) | 2002-07-25 |
EP1177206A1 (fr) | 2002-02-06 |
US20040034002A1 (en) | 2004-02-19 |
HK1047594A1 (en) | 2003-02-28 |
KR20020013530A (ko) | 2002-02-20 |
NO321536B1 (no) | 2006-05-22 |
AU4810400A (en) | 2000-11-17 |
PL351438A1 (en) | 2003-04-22 |
CN1187367C (zh) | 2005-02-02 |
NO20015262D0 (no) | 2001-10-26 |
ZA200109847B (en) | 2003-02-26 |
BR0010060A (pt) | 2002-01-15 |
YU77701A (sh) | 2005-07-19 |
UA73736C2 (en) | 2005-09-15 |
CN1360591A (zh) | 2002-07-24 |
MXPA01010915A (es) | 2002-11-07 |
HUP0201818A2 (en) | 2002-10-28 |
AU780989B2 (en) | 2005-04-28 |
CA2372342A1 (fr) | 2000-11-09 |
US20050171074A1 (en) | 2005-08-04 |
WO2000066614A8 (fr) | 2001-03-15 |
NO20015262L (no) | 2001-12-19 |
CZ20013867A3 (cs) | 2002-07-17 |
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